Pemetrexed's chemical name is (S)-2-(4(2-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido)pentanedioic acid and has the following chemical structure:

Pemetrexed disodium is the most common salt of pemetrexed di acid. It has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]benzoyl]-, disodium salt. Pemetrexed disodium heptahydrate is the active ingredient of Eli Lilly and Company's ALIMTA® injectable composition. Pemetrexed disodium heptahydrate has the following chemical structure:

Pemetrexed disodium is a multi-targeted antifolate that strongly inhibits various folate-dependent enzymes, including Thymidylate Synthase (TS), DiHydroFolate Reductase (DHFR) and GlycinAmide Ribonucleotide Formyl Transferase (GARFT). Currently, Pemetrexed disodium is commercial available in USA, European Union, Canada, Japan and China etc. for treatment of malignant pleural stromal tumor as a first-line drug, and local advanced and metastatic non-small cell lung cancer as a second-line drug. In the treatment of malignant pleural stromal tumor, Pemetrexed disodium is a unique chemotherapeutic agent in the market currently. In the second-line treatment of non-small cell lung cancer, Pemetrexed disodium has a comparative efficacy and reduced toxicities compared with the standard drug Docetaxel. Hence, it is likely for Pemetrexed disodium to become a new standard treatment of the second-line treatment for non-small cell lung cancer. In addition, the clinical studies of Pemetrexed disodium in the treatment of breast, bowel, pancreatic, head and neck, gastric and bladder cancers are still ongoing.
Various methods for preparing Pemetrexed and Pemetrexed disodium are disclosed in the art, such as WO2001014379A, WO1999016742, EP432677, EP589720, WO0011004, EP549886 and CN1778797. Luo Jie et al in U.S.20100305319A1 (equivalent: EP 2213674B1) describes a method of purifying a salt of pemetrexed have a structure of formula (III)
by salting-out, wherein if M3+ is H+, then each of M1+ and M2+ is independently H+, Li+, Na+ or K+, provided that both of them are not H+; if M3+ is Li+, Na+ or K+, then each of M1+ and M2+ is independently Li+, Na+ or K+. In example 16 and 17, it provides mention of purification of potassium pemetrexed, however, it appears that it does not refer to anything other than mono potassium salt of pemetrexed with no characterization details of the said salt. Further, in our attempt to reproduce the said example's disclosure, no material could be recovered.
First authentic disclosure of Pemetrexed Dipotassium salt, its polymorphic forms and formulations thereof is found in Indian published patent application Nos. 4322/CHE/2012, 4422/CHE/2012 and 4547/CHE/2012.
Pemetrexed being an important anticancer therapeutic agent, additional and improved ways of preparing Pemetrexed pharmaceutically acceptable salts and their polymorphs may be of immense value to pharmaceutical science and the healthcare of cancer patients.
Existence of polymorphism is known to be unique phenomenon in solid materials, wherein existence of different physical forms including shape, size, and arrangement of molecules in the physical state or polymorphs of same compound are known in the nature. A single compound, or a salt complex, may give rise to a variety of solids having distinct physical properties, which often results in substantial differences in bioavailability, stability, and other differences between production lots of formulated pharmaceutical products. Due to this reason, since polymorphic forms can vary in their chemical and physical properties, regulatory authorities often require that efforts be made to identify all forms, e.g., hydrate or anhydrate, crystalline or amorphous, solvated or un-solvated forms, etc. of the drug substances.
Some of the new polymorphic forms may turn out to be more efficacious than the other already reported forms. It has generally been observed that some forms of a compound have improved physical and chemical properties without affecting the pharmacological action of the drug and hence provide an opportunity to improve the drug performance characteristics of such product. However, the existence, and possible number, of polymorphic forms for a given compound cannot be predicted. In addition, there are no “standard” procedures that can be used to prepare different polymorphic forms of a substance.
Hence, there exists a need for the development of new stable crystalline forms and economically viable processes for preparation of Pemetrexed dipotassium, which shall be viable, industrially amenable to scale up, safer for handling, less time consuming and with better and consistent quality parameters.
The inventors of this application have found a new form of Pemetrexed i.e. Pemetrexed dipotassium (I) designated as Form-SP9, which is stable and free from any contamination.
Inventors of this application also provide a process for preparation of the said Pemetrexed dipotassium (I) Form-SP9.